The Relationship between Common Genetic Markers of Breast Cancer Risk and Chemotherapy-Induced Toxicity: A Case-Control Study

Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association...

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Bibliographic Details
Published in:	PloS one 2016-07, Vol.11 (7), p.e0158984
Main Authors:	Dorling, Leila, Kar, Siddhartha, Michailidou, Kyriaki, Hiller, Louise, Vallier, Anne-Laure, Ingle, Susan, Hardy, Richard, Bowden, Sarah J, Dunn, Janet A, Twelves, Chris, Poole, Christopher J, Caldas, Carlos, Earl, Helena M, Pharoah, Paul D P, Abraham, Jean E
Format:	Article
Language:	eng
Subjects:	Adult Aged Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Bioinformatics Biology and Life Sciences Biomarkers, Tumor - genetics Biomedical research Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - mortality Cancer Cancer therapies Chemotherapy Clinical trials Complications and side effects Deoxyribonucleic acid Disease-Free Survival DNA DNA damage Drug therapy Epidemiology Female Genes Genetic aspects Genetic diversity Genetic markers Genetic variance Genomes Health aspects Health risk assessment Health risks Hospitals Humans Laboratories Medical research Medicine Medicine and Health Sciences Metabolism Middle Aged Mutation Neuropathy Neutropenia Neutropenia - chemically induced Neutropenia - genetics Neutropenia - metabolism Neutropenia - mortality Pathways Patients Pharmacogenomic Testing Pharmacology Physiological aspects Polymorphism, Single Nucleotide Regression analysis Risk Risk Factors Single-nucleotide polymorphism Studies Survival Rate Taxanes Toxicity Womens health
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Summary:	Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.
ISSN:	1932-6203 1932-6203